Adenovirus vectors have shown promise for vaccines, but one key hurdle is preexisting immunity to these viruses in humans. The VRC has been investigating the use of DNA priming and the use of alternate adenoviral serotypes or modified adenoviral vectors to overcome prior immunity. The results demonstrate that priming with a DNA expression vector before immunization with replication-defective adenovirus vectors can overcome the limitations imposed by preexisting immunity to the viral vectors. The VRC is also evaluating various modifications to the adenovirus vector on the elicitation of cellular and humoral immunity in mice.